Alcohol abuse is a major cause of chronic pancreatitis, a severe disorder with considerable morbidity and mortality, the pathogenesis of which remains unknown and specific treatments for which do not exist. The hallmarks of chronic pancreatitis are persistent inflammation, pancreatic fibrosis and death of parenchymal cells, resulting in loss of function and glandular atrophy. Clinical evidence, as well as studies in alcohol-fed animals, suggest that alcohol uniquely promotes the transition from acute to chronic pancreatic injury by predisposing the pancreas to some, yet unknown, genetic and/or environmental factors. A key obstacle to understanding the mechanism of alcoholic chronic pancreatitis (ACP) is the lack of animal models. Recently, we have developed a model of alcohol-mediated pancreatitis in rats that for the first time reproduces the key responses of chronic human disease. In this model (termed "the CsA model of ACP"), a severe post-acute pancreatic injury, characterized by persistent inflammation, widespread fibrosis and massive loss of parenchymal cells, is induced by a synergistic effect of ethanol feeding, an episode of acute cerulein pancreatitis, and cyclosporine A (CsA) treatment. Based on our preliminary findings with this model, we propose a novel hypothesis for the pathogenesis of ACP. The hypothesis states that ACP develops because alcohol impairs the recovery from acute pancreatic injury (e.g., acute pancreatitis) by causing inadequate immunoinflammatory response (IIR). Specifically, we propose that a key molecular signal mediating alcohol- induced dysregulation of IIR in our model is inhibition of the key cytokine IFN-3, associated with inadequate innate immune response and shift in the cytokine/chemokine profile towards mediators of the pro-fibrotic Th2 and pro-inflammatory Th17 responses. These alterations result in deficient resolution of inflammation, exacerbated fibrosis, and perpetuation of the pancreatic injury. Thus, restoring a balanced, adequate IIR (e.g., by IFN-3 administration) may ameliorate alcohol-induced pancreatic injury. The proposed mechanism of ACP suggests novel targets and therapeutic strategies to treat this disorder. Overall goal: Our overall goal in this application is to test the hypothesis that dysregulation of IIR is a key mechanism of ACP, as well as to further develop our model. Specific Aims: 1. Characterize the effect of ethanol feeding on the IIR pattern in the CsA model of ACP (the innate immune response and mediators of Th1/Th2/Th17 responses). 2. Determine the role of IFN-3 in ethanol's effects on the IIR and pancreatic recovery in the CsA model of ACP. PROJECT NARRATIVE Alcohol abuse is a major cause of chronic pancreatitis, a severe disorder the mechanism of which is poorly understood and specific treatments for which do not exist. We have developed a rat model of alcoholic chronic pancreatitis that for the first time reproduces key pathologic changes of the human disease. Based on our preliminary results with this model, we hypothesize that dysregulation of immune response plays a major role in alcoholic chronic pancreatitis. The goal of our application is to test this hypothesis, which may lead to novel strategies to treat chronic pancreatitis. [unreadable] [unreadable] [unreadable]